(I) Field of Invention
The present invention relates to an improved method for converting organoboranes containing a partially optically active organyl group attached to boron, and more specifically relates to methods and intermediates for the asymmetric hydroboration of cis-alkenes, trans-alkenes and tertiary-alkenes to organoboranes containing an essentially optically pure organyl group.
Asymmetric hydroboration of alkenes, with either diisopinocampheylborane or monoisopinocampheylborane typically provides the corresponding chiral organoborane containing the new alkyl group, R*, in from 50 to 90% enantiomeric excess (ee), and occasionally in purities of from 90 to 100% ee. Because of the importance of hydroboration to, for example, the pharmaceutical industry, there has been a long standing need for a simple, reliable process which provides the alkyl group, R*, in 100% ee in all cases. The present invention fulfills that need in cases involving cis-alkenes, trans-alkenes, tertiary-alkenes and the hydroborating agents diisopinocampheylborane and monoisopinocampheylborane.
(II) Description of the Prior Art
The first successful asymmetric synthesis occured in 1961 with the hydroboration of cis-2-butene in diglyme (DG) by the chiral dialkylborane, diisopinocampheylborane to yield 2-butanol of 87% ee. Brown, H. C. et al., J. Am. Chem. Soc. 86, 397 (1964). Diisopinocampheylborane (Ipc.sub.2 BH) was prepared by the hydroboration of (+)- and (-)-.alpha.-pinene. See Brown, H. C. and Zweifel, G., J. Am. Chem. Soc., 83. 486 (1961). (FIG. 1). That landmark achievement not only provided a remarkably high asymmetric synthesis, the first of its kind, but further provided a reagent which appeared generally applicable to the asymmetric hydroboration of cis-alkenes. Brown, H. C. et al, JACS 86, 397 (1964) and Partridge, J. J., et al, JACS 95, 532 (1973). (FIG. 2)
The chiral intermediate, 2-butyldiisopinocampheylborane, was subsequently converted into optically active 2-aminobutane with complete retention of configuration and into 2-iodobutane with complete inversion of configuration. Verbit, L. et al, JOC 32, 3199 (1967) and Brown, H. C. et al, JASC 98, 1290 (1976). (FIG. 3).
In the original study of hydroborations with optically active diisopinocampheylborane, the reagent employed was prepared from commercial .alpha.-pinene of relatively low enantiomeric purity (.about.93%). Subsequent advances resulted in the preparation of reagent of high enantiomeric purity from such .alpha.-pinene. The reagent is equilibrated at 0.degree. C. with 15% excess .alpha.-pinene. The major isomer becomes incorporated into the crystalline reagent, leaving the minor isomer in solution. Brown, H. C. et al, Israel J. Chem. 15, 12 (1977). (FIG. 4). Treatment of the diisopinocampheylborane with benzaldehyde liberated .alpha.-pinene of approximately 100% ee. Thus, two reactions were developed which provided a convenient procedure for upgrading the commercial .alpha.-pinene to an enantiomeric purity of essentially 100% ee. Brown, H. C. et al, JOC 47, 4583 (1982). (FIG. 5).
Improved asymmetric results were achieved in the hydroboration of cis-alkenes with this improved reagent and a somewhat lower hydroboration temperature (-25.degree. C.). Brown, H. C. et al, JOC 47, 5065 (1982). (FIG. 6).
It has been found that while diisopinocampheylborane [(Ipc.sub.2 BH] handles cis-alkenes very effectively, it is not an effective asymmetric hydroborating agent for trans-alkenes and trisubstituted alkenes and that monoisopinocampheylborane (IpcBH.sub.2) is a more effective hydroborating agent for the latter types of alkenes.
It is difficult to halt the hydroboration of .alpha.-pinene at the monoalkylborane stage. Consequently, it was found that the monoisopinocampheylborane must be prepared by an indirect route, such as by treating diisopinocampheylborane with one-half molar equivalent of N,N,N,N-tetramethylethylenediamine (TMED) to obtain 2(IpcBH.sub.2).TMED. The diastereomeric adduct crystallizes out in enantiomerically pure form, and the pure monoisopinocampheylborane is readily liberated by treating the adduct with boron trifluoride etherate according to the method of Brown, H. C. et al, JOC 43, 4395 (1978).
Monoisopinocampheylborane has been found to be very effective for the asymmetric hydroboration of trans-alkenes (See Brown, H. C. et al, JOC 46, 5047 (1981) (FIG. 10). Similarly, the hydroboration of trisubstituted alkenes with monoisopinocampheylborane, followed by oxidation of the intermediate organoboranes, provides the corresponding alcohols in 53-72% ee, Brown, H. C. et al, JACS 99, 5514 (1977); Brown, H. C. et al., JOC 47, 5074 (1982) (FIG. 10).
For reasons that are not understood, the asymmetric hydroboration of the phenyl derivatives provides considerably improved hydroboration products of, for example 82% ee, 85% ee, 100% ee and 88% ee (FIG. 11) as compared to the 53% ee, 62% ee, 66% ee and 72% ee respectively for the corresponding parent compounds (FIG. 10), see Mandal, A. K. et al, JOC 45, 3543 (1980).
Monoisopinocampheylborane and diisopinocampheylborane are complementary to each other, and are capable of handling three of the four major classes of alkenes. Diisopinocampheylborane, a reagent with larger steric requirements, is more suited for use in the case of unhindered cis-olefins. On the other hand, hydroboration of olefins with larger steric requirements proceeds more favorably with a reagent of lower steric requirements, monoisopinocampheylborane. There still remains a need for a suitable reagent which will permit synthesis of products of high enantiomeric excess from alkenes of relatively low steric requirements, such as the 2-methyl-1-alkenes.
Initially, the application of chiral organoboranes was limited primarily to alcohols because of the presence of isopinocampheyl groups on boron in the product. Recently, it was discovered that these groups can be selectively eliminated by treatment of the mixed chiral organoboranes with acetaldehyde, regenerating the .alpha.-pinene, and providing the optically active boronate as the product. In this way, for example, 2-butyldiisopinocampheylborane is readily converted into diethyl 2-butylboranate in 97% ee. Brown, H. C. et al, JACS, 104, 4303 (1982). (FIG. 12)
Similarly, diethyl trans-2-phenylcyclopentylboronate can be obtained in 100% ee by the method of Brown, H. C. et al, JACS 104, 4303 (1982). (FIG. 13).
Hyroboration of prochiral alkenes with diisopinocampheylborane and monoisopinocampheylborane typically results in products in which approximately 60 to 90% optical activity is generally induced in the R*BIpc.sub.2 and R*BHIpc. This means that the major isomer is present in large amounts, 80-95%, and the minor isomer in much smaller amounts, 20-50%. The problem is how to separate the major isomer from the small amount of minor isomer present.
The usual organic synthesis of enantiomers produces a 50:50 mixture of the two optical isomers. Normally, these are separated by combining them with a naturally ocurring optically active acid or base (chiral auxiliary) to form a pair of diasteroisomers. Laborious fractional crystallization then separates the two diastereoisomers. The chiral auxiliary is then removed to regenerate the desired optically active compound.
However, it is not always possible to resolve optical mixtures once the final products have been obtained without destroying the molecule, and there has been a longstanding need for a reliable method of resolving the mixture at a stage to obtain an optically pure intermediate which can then be converted to any number of final products while retaining its optical configuration.
It has now been discovered that optionally pure organoborane intermediates can be reliably and readily obtained from trans-alkenes, tertiary-alkenes and monoisopinocampheylborane or cis-alkenes and diisopinocampheylborane by recrystallization of the resulting boron intermediate if solid, or first converting the liquid to a solid according to the process of the present invention. The process of the present invention not only eliminates the necessity of employing a chiral auxiliary to separate the diasteroisomers, but provides the desired organyl groups, R*, in essentially 100%ee. Consequently, the present method provides an advance in the art. By the process of this invention, it is now possible to prepare virtually any optically active compound with a chiral center, either d- or l-, in essentially 100% ee. from a cis-alkene, trans-alkene or dialkene.